PD-L1 in Systemic Immunity: Unraveling Its Contribution to PD-1/PD-L1 Blockade Immunotherapy

Bocanegra, Ana; Blanco, Ester; Fernández-Hinojal, G.; Arasanz, Hugo; Chocarro, Luisa; Zuazo, Miren; Morente, Pilar; Vera, Ruth; Escors, David; Kochan, Grazyna

doi:10.3390/ijms21165918

Cited by 18 publications

(9 citation statements)

References 106 publications

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“…The presence of PD-L1 is a negative prognostic marker 17,18 with reports of circulating PD-L1 positive monocytes, associated with some cancers. [19][20][21] Hence, we hypothesized that designing PD-L1 targeting CAR T-cells would not only be able to strike tumor cells but would also attack the PD-L1 expressing regulatory/support cells resulting in the destabilization of the cellular network that generates the immunosuppressive TME.…”

Section: Gbm Patient-derived Mc9999 Car T-cells Targeted Primary Gbm ...mentioning

confidence: 99%

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

Luo,

Garavito,

Brooks

et al. 2024

Preprint

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Chimeric antigen receptor (CAR) T-cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T-cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T-cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T-cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T-cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T-cell therapies against solid tumors.

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Section: Gbm Patient-derived Mc9999 Car T-cells Targeted Primary Gbm ...mentioning

confidence: 99%

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

Luo,

Garavito,

Brooks

et al. 2024

Preprint

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“…PD-L1 expression was mainly addressed in the context of tumor immunotherapy (reviewed in [ 66 ]). Due to its crucial role in immune regulation, it is of high interest which cells and tissues show expression of this key immune molecule in healthy tissue and diseases apart from cancer.…”

Section: Distribution Of Pd-l1 On Different Cell Types and Organsmentioning

confidence: 99%

Beyond Cancer: Regulation and Function of PD-L1 in Health and Immune-Related Diseases

Beenen

Sauerer

Schaft

et al. 2022

IJMS

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Programmed Cell Death 1 Ligand 1 (PD-L1, CD274, B7-H1) is a transmembrane protein which is strongly involved in immune modulation, serving as checkpoint regulator. Interaction with its receptor, Programmed Cell Death Protein 1 (PD-1), induces an immune-suppressive signal, which modulates the activity of T cells and other effector cells. This mediates peripheral tolerance and contributes to tumor immune escape. PD-L1 became famous due to its deployment in cancer therapy, where blockage of PD-L1 with the help of therapeutic antagonistic antibodies achieved impressive clinical responses by reactivating effector cell functions against tumor cells. Therefore, in the past, the focus has been placed on PD-L1 expression and its function in various malignant cells, whereas its role in healthy tissue and diseases apart from cancer remained largely neglected. In this review, we summarize the function of PD-L1 in non-cancerous cells, outlining its discovery and origin, as well as its involvement in different cellular and immune-related processes. We provide an overview of transcriptional and translational regulation, and expression patterns of PD-L1 in different cells and organs, and illuminate the involvement of PD-L1 in different autoimmune diseases as well as in the context of transplantation and pregnancy.

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“…The PD-L1/PD1 axis has an important impact not only on T cells but also on cancer cells and MDSCs. PD-L1, expressed on cancer cells and MDSCs [ 72 ], drives a high rate of glycolysis causing glucose depletion from the TME, and impairing T cell activation. PD-L1 blockade impacts on tumor glycolytic pathway by inhibiting the PI3K/mTOR signaling and decreasing the expression of GLUT1, with a subsequently increased availability of glucose in the TME, favoring the metabolism of activated T cells and restoring IFNγ production [ 73 ].…”

Section: The Intimate Interplay Between Gbm and Mdscs Is Detrimental To Tilsmentioning

confidence: 99%

Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

Ianni

Musio

Pellegatta

2021

IJMS

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The metabolism of glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is flexible and adaptable to different adverse conditions, such as nutrient deprivation. Beyond glycolysis, altered lipid metabolism is implicated in GBM progression. Indeed, metabolic subtypes were recently identified based on divergent glucose and lipid metabolism. GBM is also characterized by an immunosuppressive microenvironment in which myeloid-derived suppressor cells (MDSCs) are a powerful ally of tumor cells. Increasing evidence supports the interconnection between GBM and MDSC metabolic pathways. GBM cells exert a crucial contribution to MDSC recruitment and maturation within the tumor microenvironment, where the needs of tumor-infiltrating lymphocytes (TILs) with antitumor function are completely neglected. In this review, we will discuss the unique or alternative source of energy exploited by GBM and MDSCs, exploring how deprivation of specific nutrients and accumulation of toxic byproducts can induce T-cell dysfunction. Understanding the metabolic programs of these cell components and how they impact fitness or dysfunction will be useful to improve treatment modalities, including immunotherapeutic strategies.

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PD-L1 in Systemic Immunity: Unraveling Its Contribution to PD-1/PD-L1 Blockade Immunotherapy

Cited by 18 publications

References 106 publications

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

Beyond Cancer: Regulation and Function of PD-L1 in Health and Immune-Related Diseases

Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

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